Excessive accumulation of Abeta protein in beta-amyloid deposits is a hallmark event in Alzheimer's disease (AD). In recent years, some of the most promising therapeutic strategies for potentiating beta-amyloid clearance has involved the use of anti-Abeta antibodies. In transgenic animal models of AD beta-amyloid deposition can be inhibited by either peripheral infusion of exogenous anti-Abeta antibodies (passive) or autoimmunity induced by immunization with synthetic Abeta peptide (active). Unfortunately, the latter approach has been associated with potentially fatal complications involving inflammation of the CNS vasculature in humans. While experiments to date have employed unmodified monomeric Abeta to test for autoimmunity, up to 40 % of the Abeta pool in AD brain consists of low molecular weight oligomeric cross-linked beta-amyloid protein species (CAPS). Moreover, numerous lines of evidence have implicated soluble CAPS as the primary neurotoxic agent in AD. We have recently reported that while levels of autoantibodies to monomeric Abeta are similar in the plasma of AD and non-demented control subjects, autoantibodies to CAPS are significantly reduced in AD patients. In addition, age-at-onset for AD correlates with plasma immunoreactivity to CAPS. Based on these findings, we hypothesize that the sub-pool of Abeta autoantibodies targeted at CAPS may normally provide a natural defense against AD pathogenesis, but are depleted in AD patients. Accordingly, replenishing the level of anti-CAPS antibodies could potentially provide therapeutic benefit for AD. In the proposed study we plan to a) identify CAPS with the highest neurotoxic potential, b) select single-chain fragment variable antibodies (scFvs) specific for the most neurotoxic CAPS using recombinant phage display system to identify CAPS-specific immunoreactive scFvs from a vector library of over 10^12 human derived antibodies, and, c) test anti-CAPS scFv antibodies for activity in attenuating CAPS neurotoxicity in primary cultures of cortical neurons. We posit that targeting soluble CAPS with human derived antibodies may have distinct advantages over previous vaccine-based AD treatment strategies that have employed more generic anti-Abeta antibodies. Finally, with regard to passive immunization therapies, by specifically targeting the Abeta species that are most relevant to AD pathology, lower anti-Abeta antibody titers might be prescribed, thereby attenuating potential side-effects associated with inflammation. [unreadable] [unreadable] [unreadable]